Heart disease remains the leading cause of death worldwide, accounting for nearly 30% of the annual total (i.e., approximately 15 million people). Heart and vascular disease debilitate many more individuals every year. For many, atherosclerotic disease is a life-long process; it may possess an initial stage in childhood, without clinical manifestation until middle age or later. Its development has been repeatedly linked to unhealthy lifestyles (e.g., tobacco use, unbalanced diet, and physical inactivity). Much progress has been made in the detection and treatment of various forms of heart and vascular disease, but preventative measures and assorted treatment regimens are usually incapable of halting or curing the underlying disease condition.
Atherosclerosis is now recognized to be a chronic inflammatory disease characterized by subendothelial accumulation of atherogenic lipoproteins, extracellular matrix, neovessels, calcium, and inflammatory cells. Activation of inflammatory genes in the vessel wall with subsequent adhesion, chemoattraction, subendothelial migration, retention, and activation of inflammatory and immune cells such as monocytes and T cells are believed to play a critical role in the initiation, progression, and destabilization of atherosclerosis (Ross, R. (1999) N. Engl. J. Med. 340, 115-126; Glass, C. K. & Witztum, J. L. (2001) Cell 104, 503-516; Shah, P. K. (2003) J. Am. Coll. Cardiol. 41, 15S-22S; Libby, P. (2002) Nature 420, 868-874; Hansson, G. K., et al. (2002) Circ. Res. 91, 281-291; Binder, C. J., et al. (2002) Nat. Med. 8, 1218-1226). Increasing interest has focused on the potential role of infectious agents and components of the innate immune system as contributors to atherosclerosis (Kol, A. & Libby, P. (1998) Trends Cardiovasc. Med. 8, 191-199), but clinical trials investigating treatment of cardiovascular diseases with antibiotics have produced conflicting results (Sander, D., et al., (2004) Circulation 109, 1010-1015; Zahn, R., et al. (2003) Circulation 107, 1253-1259; Sander, D., et al. (2002) Circulation 106, 2428-2433), perhaps because of inadequate power to detect differences or other shortcomings (Grayston, J. T. (2003) Circulation 107, 1228-1230).
Notwithstanding clinical disappointments, experimental evidence has accumulated that suggests that with enhanced understanding, treatment of cardiovascular disease with antibiotics and/or immunization may one day become feasible (Fredrikson, G. N., et al. (2003) Arterioscler. Thromb. Vasc. Biol. 23, 879-884; Binder, C. J., et al. (2003) Nat. Med. 9, 736-743; Hansson, G. K. (2002) Circulation 106, 1599-1601). In particular, intriguing data from animal studies suggest the potential importance of toll-like receptors (TLRs) and other key components of the innate immune system in atherosclerosis-based pathologies (Michelsen, K. S. et al. (2004) J. Immunol. 173, 5901-5907; de Kleijn, D. & Pasterkamp, G. (2003) Cardiovasc. Res. 60, 58-67). TLRs are a family of receptors that activate proinflammatory signaling pathways in response to microbial pathogens or pathogen-associated molecular patterns. Ligand binding to TLRs results in the recruitment of the adaptor molecule myeloid differentiation factor 88 (MyD88) to the toll/IL-1 receptor domain of the receptor. Intracellular propagation of the signal leads to activation of the transcription factor NF-κB, thereby influencing inflammatory responses (Zhang, G. & Ghosh, S. (2001) J. Clin. Invest. 107, 13-19). Furthermore, studies have shown that TLRs that signal through MyD88 are essential in proinflammatory cytokine responses to many microbial pathogens. Del Rio, L. et al. (2004) J Immunol. 172, 6954-60. MyD88 is an adapter protein necessary for the biochemical signaling attributed to a variety of cell receptors, including, by way of example, TLRs such as TLR4, as well as interleukin-1 (IL-1) and interleukin-18 (IL-18).
Studies have shown that human and murine lipid-rich atherosclerotic plaques express TLR4, and that TLR4 expression in macrophages is up-regulated by oxidized but not native low-density lipoprotein (LDL) (Xu, X. H., et al., (2001) Circulation 104, 3103-3108; Edfeldt, K., et al. (2002) Circulation 105, 1158-1161). In vitro studies have demonstrated that minimally modified LDL (MM-LDL), a proinflammatory and proatherogenic lipoprotein, is recognized by TLR4 and the coreceptor CD14 on macrophages, and binding of this lipoprotein leads to actin polymerization and spreading of macrophages (Miller, Y. I., et al. (2003) J. Biol. Chem. 278, 1561-1568). In human endothelial cells (ECs), the recognition of MM-LDL by TLR4 results in the secretion of IL-8, a chemokine important in monocyte transmigration and retention in the vessel wall (Walton, K. A., et al. (2003) J. Biol. Chem. 278, 29661-29666). However, this effect of MM-LDL was CD14-independent. Patients expressing a polymorphism in the TLR4 gene manifest lipopolysaccharide (LPS) hyporesponsiveness, are protected from carotid artery atherosclerosis and acute coronary events (Arbour, N. C., et al., (2000) Nat. Genet. 25, 187-191; Kiechl, S., et al. (2002) N. Engl. J. Med. 347, 185-192; Kiechl, S., et al., (2003) Ann. Med. 35, 164-171; Ameziane, N., et al. (2003) Arterioscler. Thromb. Vasc. Biol. 23, 61-64), and derive greater benefit from risk reduction with statins (Boekholdt, S. M., et al. (2003) Circulation 107, 2416-2421). Collectively, these findings suggest that TLR signaling may play a role in the development of atherosclerotic plaques.
Conventional treatments for vascular disease have substantial drawbacks; many are only partially effective, and few provide a true cure for associated conditions. There remains a clear need in the art for a method of preventing, treating, and curing vascular disease, including atherosclerosis.
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